1. Field of the Invention
The present invention is in the field of methods of treating asthma. And more particularly, the present invention is in the field of treating asthma with pharmaceutical compounds which prevent or inhibit the basic progress of the disease, as opposed to methods of treatment which are merely palliative.
Bronchial asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airways diameter has been implicated. Persons manifesting such imbalance have hyperractive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such persons are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors, e.g., changes in barometric pressure or temperature, inhalation of cold air or irritants, e.g., gasoline fumes, fresh paint and noxious odors, or cigarette smoke, exposure to specific allergens, and ingestion of aspirin or sulfites in sensitive individuals. Psychologic factors may aggravate an asthmatic attack but are not assigned a primary etiologic role.
Asthmatic attacks are characterized by narrowing of large and small airways due to spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa, and production of tenacious mucus. The role of inflammation in the perpetuation of the abnormal airway responses (late-phase reaction) is only now being appreciated.
Mechanisms underlying bronchoconstriction are not well defined. However, an imbalance between .beta.-adrenergic and cholinergic control of airways diameter has been proposed. In turn, the observed abnormalities in adrenergic and cholinergic functions in asthma appear to be controlled by the cyclic 3',5'-adenosine monophosphate (cyclic AMP or cAMP)-cyclic 3',5'-guanosine monophosphate (cyclic GMP or cGMP) systems within various tissues, e.g., mast cells, smooth muscle, and mucus-secreting cells. The intracellular concentration of cAMP is a principal determinant of both smooth muscle relaxation and inhibition of IgE-induced release of several mediators, which cause bronchoconstriction either directly or by cholinergic reflex action and increases exocrine section.
Antigen challenged allergic sheep are a standard animal model for human asthma, having the capability to measure the immediate bronchoconstriction and the important late phase response. Surprisingly, (S)-.alpha.-fluoromethylhistidine, in this model, dosed intravenously or by inhaled aerosol, virtually eliminated the late phase response. Since commonly used antiasthma drugs are active in this model, (S)-.alpha.-fluoromethylhistidine is expected to have antiasthma activity in man.
2. Brief Description of the Prior Art
Drug treatment for asthma includes oral phosphodiesterase inhibitors, oral and inhaled .beta.-adrenergic agonists, oral and inhaled steroids, and inhaled inhibitors of mediator release.